1-cyano-benzocyclobutenes

ABSTRACT

IN WHICH Ph represents a substituted orthophenylene radical and R&#39;&#39; hydrogen or a substituted or unsubstituted alkyl radical, for example 1-cyano-benzocyclobutene. Use: intermediates for the preparation of the corresponding 1-(aminomethyl)benzocyclobutenes which possess analgesic, particularly antimorphine activity and also antitussive activity.   Compounds of the formula

United States Patent Erwin Friedrich Jenny Riehen;

Karl Schenker, Basel, both of Switzerland 680,350

Nov. 3, 1967 Nov. 23, 197 l CIBA Corporation New York, NY.

Original application Mar. 18, 1966, Ser. No. 535,368, now Patent No.3,377,347, Continuation-impart of application Ser. No. 297,675, J uiy25, 1963, now abandoned. Divided and thk application Nov. 3, 1967, Ser.No. 680,350

Inventors Appl. No. Filed Patented Assignee l-CYANO-BENZOCYCLOIBUTENES 5Claims, No Drawings Int. Cl ..C07C 87/02, C07C 121/64 OTHER REFERENCESCava et al., J. Am. Chem. Soc. Vol. 80, p. 2260 1958). Bunnett et al.,J. Org. Chem. Vol. 27, pp. 3836- 3838, (1962) Primary Examiner-CharlesB. Parker Assistant Examiner-Dolph l-l. Torrence Attorneys-HarryGoldsmith, Joseph G. Kolodny and Bryant W. Brennan ABSTRACT: Compound ofthe formula R GEN in which Ph represents a substituted orthophenyleneradical and R hydrogen or a substituted or unsubstituted alkyl radical,for example 1-cyano-benzocyclobutene. Use: intermediates for thepreparation of the corresponding 1- (aminomethyl)benzocyclobutenes whichpossess analgesic, particularly antimorphine activity and alsoantitussive activity.

l-CYANO-BENZOCYCLOBUTENES CROSS-REFERENCE TO RELATED APPLICATIONS Thisis a divisional application of our copending application Ser. No.535,368, filed Mar. 18, 1966 (now U.S. Pat. No. 3,397,347) which in turnis a continuation-in-part of our application Ser. No. 297,675, filedJuly 25, 1963 (now abandoned).

The present invention relates to new benzocyclobutene derivatives. Moreespecially it concerns benzocyclobutenes of the formula R CHI Y in whichPh represents and o-phenylene radical, Y an amino group and R stands forhydrogen or a substituted or unsubstituted alkyl radical, and theirsalts.

The o-phenylene radical Ph may be unsubstituted or mono, diorpolysubstituted. Substituents are primarily alkyl groups, for examplelower alkyl groups such as methyl, ethyl, propyl, butyl, pentyl or hexylgroups, hydroxyl groups, alkoxy groups, for example lower alkoxy groupssuch as methoxy, methylenedioxy, ethoxy', propoxy, or butoxy groups,acyloxy groups, for example hydroxyl groups substituted by the acylradicals mentioned below, amino groups such as free or acylated aminogroups, for example amino groups substituted by the under-mentioned acylradicals, or monoor dilower alkylated amino groups, for example aminogroups substituted by the alkyl groups mentioned above, nitro groups,halogen atoms or trifluoromethyl groups.

Alltyl radicals R are more especially the aforementioned. Substituentsof the alkyl radical R are, for example, hydroxyl groups, lower alkoxygroups, for example, those mentioned above, free or substituted aminogroups, for example those mentioned above, or free or functionallyconverted carboxyl groups, such as cyano groups or esterified carboxylgroups, for example carbalkoxy groups, such as lower carbalkoxy groups,for example the carbethoxy group.

The amino group Y may be free or disubstituted. or disubstituted. Assubstituents there are especially suitable substituted or unsubstitutedhydrocarbon radicals, above all aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic hydrocarbon radicals which maybe interrupted by hetero atoms such as oxygen, sulfur or nitrogen, beingfor instance alkyl, oxaalkyl, alkenyl, alkinyl, alkylene, oxaalkylene,azaalkylene, thiaalkylene, cycloalkyl, cycloalkenyl, cycloalkenyl-alkylgroups, oxacycloalkyl-alkyl, aralkyl or aralkenyl radicals. As examplesthere may be mentioned lower alkyls such as methyl, ethyl, propyl,isopropyl, linear or branched butyl, pentyl, hexyl or heptyl groupsbound in any desired position, lower oxaalkyl radicals such as3-oxabutyl, 3-oxapentyl or 3-oxaheptyl radicals; lower alkenyl radicalssuch as allyl or methallyl, lower alkinyl radicals, such as thepropargyl radical: lower alkylene radicals which may also contain afused-on benzene ring, such as butylene-( 1:4), butylene-( 1:5),hexylene-( 1:5), hexylenel( l :6), hexylene-(2z5), heptylene- 1:7),heptylene-(2.7), benz (2:3),-pentamethylene-(l:5)-, heptylene-(2z6);lower oxa-alkylene or azaalkylene radicals such as 3-oxaor3-aza-pentylene-( l :5), 3-oxaor 3-aza-hexylene-( 1:6), cyclopentyl,cyclohexyl, cyclopentyl or cyclohexenyl radicals, cyclopentyl-,cyclohexyl-, cyclopentyl-, cyclohexenyl-methyl or -ethyl radicals;furyl-lower alkyl radicals, such as the furfuryl radical, phenyl-loweralkyl or phenyllower alkenyl radicals which may also be substituted, forexample in the manner defined above for the benzene nucleus, and/orinterrupted by hetero atoms, for example those mentioned above, beingfor example benzyl, phenyl ethyl, phenyl propyl or anilino ethyl oranilino propyl groups. A substituted amino group Y is primarily a monoordilower alkylamino group, such as the methylamino, dimethylamino,ethylamino or diethylamino group, a phenyl-lower alkylamino groups suchas the B-phenylethylamino group, or a benzylamino group, an N-loweralkylphenyl-lower alkylamino group such f 1 cm-n R1-- where R representsa free or substituted amino group, such as a monoor dialkylamino group,a pyrrolidino, piperidino, morpholino, thiamorpholino or piperazinogroup or a phenyllower alkylamino group; R, represents hydrogen, loweralkyl, hydroxyl, lower alkoxy, halogen or trifluoromethyl and R,

represents a lower alkyl group or preferably hydrogen, especially thecompounds of the formula in which R stands for hydrogen or lower alkoxy,R, for lower alkyl or hydrogen and R, for lower alkyl or preferably forhydrogenand particularly the l-aminomethyl-benzocyclobutene.

Especially valuable with respect to its pharmacological properties isthe l-(ethylaminomethyl)-5-methoxy-benzocyclobutene of the fonnulawhich, in addition to its analgesic, particularly antimorphine, action,which it displays in the animal test, for example on mice, has anantitussive effect e.g. on cats and an elective inhibitory effect onexpiratory activities as has been shown in animal tests, for example onthe narcotized pigeon after tracheal blockage. This compound, in thefree form or in the form of its salts, is consequently not only usefulas an analgesic but also as an antitussive. Thus, for example, when thehydrochloride of the new compound is given intravenously in dosages from3 to 10 mg. per kgJof bodyweight to the eat it displays a distinctantitussive effect and produces in a dosage of only 0.3 mg. per kg.bodyweight in the pigeon a pronounced inhibitory efi'ect uponexpiratoryactivities, and in a dosage of as little as 0.3 mg. per kg. bodyweightin the rabbit a distinct morphine-antagonistic effect.

The new compounds are obtained by methods known per se, preferably byreducing a compound of the formula R ON in which Ph and R have themeanings given above, and, if desired substituting the free amino groupin a resulting compound.

The reduction' is carried out in the usual manner, for example withnascent hydrogen or with catalytically activated hydrogen, such ashydrogen in the presence of a metal catalyst, such as a palladium,nickel or platinum catalyst, or with a complex metal hydride, such'aslithium aluminum hydride.

Another process for the manufacture of the new compounds consists inreducing a compound of the formula in which Ph, R and Y have themeanings given above, or in reducing a compound of the formula in whichPh and R have the meanings given above and y' represents an aeylaminogroup, such as an alkanoylamino group, for example a lower alkanoylaminogroup, such as an acetylamino, propionylamino or butyrylamino group, ora benzoylamino group or phenyl-lower alkanoylamino group in which thephenyl nucleus may be substituted in the manner shown above for theo-phenylene radical. The reduction can be achieved, for example, byreaction with a di-light metal hydride, more especially an alkalimetal+aluminum hydride, such as lithium aluminum hydride.

Another method for preparing the new compounds consists in reacting acompound of the formula in which Ph, R and R have the meanings givenabove and X represents a reactive esterified hydroxyl group with ammoniaor an amine of the formula HY, Y having the meaning given above.Reactive esterified hydroxyl groups are, for example, hydroxyl groupswhich are esterified with strong inorganic organic acids, preferablywith a hydrohalic acid, such as hydrochloric, hydrobromic, or hydriodieacid, or with an arylsulfonic acid, such as benzenesulfonic ortoluenesulfonic acid.

The above-mentioned reactions are conducted in known manner, in thepresence or absence of diluents and/or condensing agents, at roomtemperature or below or above it, under atmospheric or superatmospheriepressure.

In the resulting compounds further substituents may be introduced orsubstituents already present therein may be eliminated or converted.Thus, a compound in which the amino group of the l-aminomethyl radicalcontains at least one hydrogen atom may be substituted, for examplealkylated. The alkylation may follow the usual practice and consist, forexample, in the reaction with a reactive ester of an alcohol, such as alower alkanol or aralkanol, such as lower alkyl or aralkyl halides orsulfates, or corresponding esters of sulfonic acids, for example methyl,ethyl, propyl, isopropyl or benzyl chloride, bromide or iodide, dimethylor diethyl sulfate, methane-, ethaneor paro-toluene acid methyl or ethylester or by reductive alkylation, that is to say, by reaction with anoxo compound followed or accompanied by reduction. The reduction isperformed in the usual manner, for example with hydrogen in the presenceof a catalyst, such as platinum, palladium or nickel catalyst. A Schiffsbase obtained as the condensation product may alternatively be reducedwith an alkali metal-earth metal hydride, such as sodium borohydride orlithium aluminum hydride.

Compounds that contain a free hydroxyl group at the benzene nucleus maybe alkylated or acylated by aknown method. The alkylation may be carriedout, for example, by reaction with a reactive ester of an alkanol,preferably in the presence of a strong base, The acylation is performedby reac tion with an acid, preferably used in the form of a functionalderivative thereof.

ln compounds that contain at the benzene nucleus acyloxy or alltoxygroups, the acyl and alkyl groups respectively can be removed byhydrolysis.

The aforementioned reactions are performed in known manner, in thepresence or absence of diluents and/or a condensing agent, at roomtemperature or below or above it, under atmospheric or superatmosphericpressure.

The invention further includes any variant of the present process inwhich an intermediate obtainable at any stage of the process is used asstarting material and any remaining step or steps is/are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reactants are used, if desired, in the form of their salts.

Depending on the reaction conditions and the starting materials used,the final products are obtained in the form of the free bases or in theform of their salts which are also included within the scope of theinvention. For example, basic,

neutral, acid or mixed salts, if desired also hemi-, mono-, sesquiorpolyhydrates thereof may be obtained. The salts of the final productsmay be converted in a manner known per se, for example with an alkali oran ion exchange resin, into the free bases. From the latter, salts maybe obtained by reaction with an organic or inorganic acid, particularlyan acid which is suitable for the formation of therapeuticallyacceptable salts, such acids are, for example: hydrohalic acids,sulfuric acids, phosphoric acids, nitric acid, perchloric acid:aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonicacids, such as formic, acetic, propionic, succinic, glycollic, lactic,malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvicacid; phenylacetic, benzoic, paminobenzoic, anthranilic,p-hydroxybenzoic, salicylic or paminosalicylic acid, embonic acid,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonicacid; halogenbenzenesulfonic, toluenesulfonic, naphthalenelulfonic acidsor sulfanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, for example the picrates, mayalso be used for purifying the resulting bases by converting the baseinto a salt, isolating the latter and liberating the base from the saltagain. In view of the close relation between a base in the free form andin the fonn of a salt thereof, whenever a free base is referred to inthis context, a corresponding salt is also intended,- provided such ispossible or appropriate under the circumstances.

The reactions of the invention are advantageously performed with thosestarting materials which give rise to the preferred compounds referredto above.

The starting materials are known or can be prepared by known methods.

The lcyano-benzocyclobutenes used as starting material are obtained, forexample, by subjecting a B-[orthohalogenophenyll-propionitrile tointramolecular condensation in the presence of potassium amide, or bybrominating a benzocyclobutene in position 1 with N-bromo-succinimide,followed by exchange of the bromine atom for a cyano group by means ofsodium cyanide.

Those benzocyclobutenes, used as starting material, which contain anacid amide group in position 1, can be prepared by hydrolyzing thenitrile group in l-cyanobenmcyclobutenes to the carbamyl group, or byhydrolyzing the nitrile group to the carboxyl group, converting thelatter to an acid halide grouping or ester grouping, and reacting thelatter groupings with ammonia or with an amine containing at least onehydrogen atom. Starting materials that contain in position 1 a reactiveesterified hydroxymethyl group are obtained, for example, by convertingin a l-cyano-benzocyclobutene the nitrile group into a carbalkoxy groupin known manner, reducing the latter to the hydroxymethyl group andreactively esterifying the hydroxyl group in the latter. Alternatively,l-hydroxymethyl compounds can also be manufactured by reducing abenzocyclobutene that contains in position 1 an acyl group.

Any new starting material is likewise included in the present invention.

The new compounds may be used as medicaments for example in the form ofpharmaceutical preparations containing them in free form or in form oftheir salts in admixture or conjunction with an organic or inorganic,solid or liquid excipient suitable for enteral or parenteraladministration. Suitable excipients are substances that do not reactwith the new compounds, for exam le water, gelatine, lactose, starches,stearyl alcohol, magnesium stearate, talcum, vegetable oils, benzylalcohols, gums, propylene glycol, polyalkylene glycols, white petroleumjelly, cholesterol or other known medicinal excipients. Thepharmaceutical preparations may be, for example, tablets, dragees orcapsules, or in liquid form solutions, suspensions or emulsions. Theymay be sterilized and/or may contain assistants, such as preserving,stabilizing, wetting or emulsifying agents, solutions promoters or saltsfor regulating I the osmotic pressure, or buffers. They may also containother EXAMPLE 1 2l.2 g. of l-cyano-benzocyclobutene in 120 ml. ofabsolute ether are added dropwise to 6.2 g. of lithium aluminum hydridein 260 ml. of absolute ether with ice-cooling and stirring. The reactionmixture is then heated for 45 minutes at the boil. While cooling withice and stirring there are then cautiously dropped in successivelyice-cooling ml. of water, 6.2 ml. of sodium hydroxide solution ofpercent strength and l8.6 in]. of water. The batch is thensection-filtered and the filter cake is rinsed with ether. The combinedfiltrates are dried over sodium sulfate and evaporated under a water-jetvacuum at 30 to 40 C. The liquid radical is distilled under a water-jetvacuum, to yield l-aminomethyl-benzocyclobutene of the formula EXAMPLE 213.3 g. of l-aminomethyl-benzocyclobutene are added dropwise to 25.5 g.of aqueous formic acid of 90 percent strength while cooling with ice. Aboiling stone and 22.5 g. of aqueous formaldehyde solution of 37 percentstrength are added to this solution and the flask is immersed in an oilbath previously heated to 90-l00 C. After a few minutes a vigorousevolution of carbon dioxide sets in. When this strongly exothermicreaction has subsided, the flask is removed from the oil bath, and thebatch is then maintained for 6 hours at 90l00 C. While cooling with ice,50 ml. of 4N-hydrochloric acid are added. The reaction mixture is thenevaporated under a water-jet vacuum and the reside is taken up in 30 ml.of water. The aqueous solution is alkalinized with 25 ml. of l8N-sodiumhydroxide solution while being cooled with ice and then extracted withether. The ethereal solution is washed with water until the washings runneutral, dried over sodium sulfate and evaporated. The liquid amine isconverted into its hydrochloride with hydrogen chloride in absoluteethyl acetate. After recrystallization from alcohol+ethyl acetate+ether,l-dimethylaminonethyl-benzoyclobutene hydrochloride of the formulamelting at l57-l 58 C. is obtained.

EXAMPLE 3 In a half-liter autoclave 25.9 grams ofl-cyano-benzocyclobutene in 100 ml. of liquid ammonia and 100 ml. ofabsolute alcohol are hydrogenated in the presence of 2.5 grams of Raneynickel under a pressure of atmospheres of hydrogen at C. When thereaction mixture is heated, the pressure rises to atmospheres and thendrops within 30 minutes to 75 atmospheres. The autoclave is cooled,atmospheric pressure is restored, the catalyst filtered off and thefiltrate evaporated at a water-jet vacuum at 30 C. The oily radical isdistilled and yields l-aminomethylbenzocyclobutene boiling at 97-98 C.at l2 mm. pressure of mercury. The product is identical with thatdescribed in example I.

EXAMPLE 4 A solution of 2.27 grams of N-furfuryl-benzocyclobutene-(l)-carboxylic acid amide in 20 ml. of absolute tetrahydrofuran is addeddropwise to 1 gram of lithium aluminum hydride in 20 ml. of absolutetetrahydrofuran. The reaction mixture is boiled for 20 hours, cooled,and then treated successively with 1 ml. of water, 1 ml. of sodiumhydroxide solution of IS percent strength and 3 ml. of water. Theprecipitate is filtered with suction and the filtrate dried over sodiumsulfate and then concentrated. The residue is distilled at l25 C. under0.2 mm. pressure of mercury and converted with hydrogen melting at 205C.

The N-furfuryl-benzocyclobutene-(l)-carboxylic acid amide used asstarting material may be prepared as follows:

1.66 grams of benzocyclobutenyl-(l )-carboxylic acid chloride in 10 ml.of absolute methylene chloride are added dropwise to 0.97 gram offurfurylamine and 0.81 ml. of absolute pyridine in 25 ml. of absolutemethylene chloride. After 30 minutes, the reaction 'mixture is washedwith 2N- hydrochloric acid, 2N-sodium carbonate solution and water. Theorganic phase is dried over sodium sulfate filtered and evaporated. Thecrystalline residue is recrystallized from xylene and yieldsN-furfuryl-benzocyclobutene-( l )-carboxylic acid amide in the form ofcolorless needles melting at l04l0 6C.

The above described acid chloride is obtained by conventional methodsfrom the corresponding acid and thionyl chloride. It is a colorlessliquid; boiling point l03-l05 C. under 12 mm. pressure of mercury.

EXAMPLE 5 15.1 grams of l-acetylaminomethyl-benzocyclobutene in ml. ofabsolute tetrahydrofuran are added dropwise and with stin'ing to 6.8grams of lithium aluminum hydride in l70 ml. of absolutetetrahydrofuran. The reaction mixture is then boiled for 6 hours underreflux, cooled, and 6.8 ml. of water. 6.8 ml. of sodium hydroxidesolution of l5 percent strength and 20.3 ml. of water are addeddropwise. The precipitate is filtered with suction, and the filtrateevaporated at a water-jet vacuum. The oily reside is treated withhydrogen chloride in ethyl acetate, the crystallinel-ethylaminomethyl-benzocyclobutene hydrochloride of the formula CHgNHCH5 ing material may be obtained as follows:

60 ml. of freshly distilled acetic anhydride are added dropwise withice-cooling and stirred to a mixture of 12.0 grams ofl-aminomethyl-benzocyclobutene and 7.9 grams of absolute pyridine. Thereaction mixture is allowed to stand overnight at room temperature andthen evaporated at 60-70 C. at a water-jet vacuum. The residue is takenup in ether and washed six times with saturated aqueous sodiumbicarbonate solution. The ether solution is then dried over sodiumsulfate and evaporated. The oily residue is distilled in a bomb tube(bath temperature I l5l 20 c; 0.02 mm. pressure of mercury) and yieldsl-(acetylaminomethyl)-benmcyclobutene as a colorless distillate whichcrystallizes spontaneously and can be recrystallized either from wateror methylene chloridet-petroleum ether; melting point: 72-75 C.

EXAMPLE 6 9.0 grams of crude l-[a-aniloinoacetyl)aminomethyl]-benzocyclobutene is dissolved in 80 ml. of absolute tetrahydrofuran andslowly added dropwise to a solution of 3.5 grams of lithium aluminumhydride in 80 ml. of absolute tetrahydrofuran. The reaction mixture isboiled for 20 hours, and then treated in succession with 3.5 ml. ofwater, 3.5 ml. of sodium hydroxide solution of 15 percent strength and10.5 ml. of water. The precipitate is filtered off and the filtratedried over sodium sulfate. The solvent is expelled to yield l-[(B-anilinoethyl)-aminomethyll-benzocyclobutene of the formula CH -NH-CH -CH-NHQ 0 Cm-NE-ii-OHFNHQ EXAMPLE 7 28.0 grams ofl-[phenylaeetylaminomethyl1-benzocyclobutene are dissolved in 100 ml. ofabsolute tetrahydrofuran and slowly added dropwise to a mixture of 4.0grams of lithium aluminum hydride in I00 ml. of absolutetetrahydrofuran. The

reaction mixture is boiled for 20 hours and then worked up by the methoddescribed in example 6. The oily residue is treated in ethyl acetatewith the calculated quantity of hydrochloric acid to yieldl-[(B-phenylethyl)-aminomethyll-benzocyclobutene hydrochloride of theformula om-nn-om-cm-Q melting at 256 to 258 C.

The l-[phenylacetylaminomethyll-benzocyclobutene used as startingmaterial may be prepared as follows:

54.6 grams of phenylacetyl chloride in ml. of absolute methylenechloride are added dropwise to a mixture of 42.8 grams ofl-aminomethyl-benzocyclobutene, 35.8 grams of triethylamine and 850 ml.of absolute methylene chloride. When the addition is complete, thereaction mixture is stirred for 15 minutes at room temperature. Theclear reaction solution is then washed in succession withZN-hydrochloric acid, ZN-sodium carbonate solution and water, dried oversodium sulfate, filtered and evaporated. The residue is distilled toyield l-[phenylacetylaminomethyll-benzocyclobutene as a colorless solidsubstance melting at 75-79 C., and boiling at 158 C., under 0.06 mm.pressure of mercury.

EXAMPLE 8 27 grams of lithium aluminium hydride are cautiously mixedwith 600 ml. of absolute tetrahydrofuran while being stirred and cooledwith ice. 69 grams of l- (acetylaminomethyl)-5-methoxy-benzocyclobutenein 600 ml. of absolute tetrahydrofuran are then stirred in withoccasional cooling. The reaction mixture is then boiled for 10 hoursunder dry nitrogen and allowed to cool. While cooling with ice andstirring vigorously, 27 ml. of water, then 27 ml. of sodium hydroxidesolution of 15 percent strength and finally 8] ml. of water arecautiously dropped in. The precipitate formed is suctioned of? throughCelite. The filter cake is rinsed with tetrahydrofuran. The filtrate isdried over sodium sulfate, filtered and evaporated under vacuum. Theresulting CHJO ' -HCl precipitates in the form of a colorless salt. Onrecrystallization from alcohoH-ethyl acetate it forms colorless crystalsmelting at l'69to l7lC. I

The l-(acetylaminomethyl)-5-methoxy-benzocyclobutene used as startingmaterial may be prepared in the following manner:

While cooling a mixture of 62 g. of l-(amin'omethyI)-5-.methoxy-benzocyclobutene and 30 g. of absolute pyridine, 300 ml. offreshly distilled acetic anhydride are stirred in at a rate such thatthe internal temperature does not rise above 40 to 50 C. The batch isthen left to itself for 4 hours at room temperature and evaporated undervacuum at 60 to 70 C. The residue is taken up in ether and repeatedlyagitated with sodium bicarbonate solution. The ethereal solution isdried over sodium sulfate, filtered and evaporated. The residue, l-(acetylaminomethyl)-5-methoxy-benzocyclobutene, is dried under a highvacuum. It is used for the reduction with lithiumaluminium hydridewithout first having been purified.

EXAMPLE 9 8.65 grams of I-(p-toluenesulfonyloxymethyl)-benzocyclobutenein l0.0 ml. of absolute benzene are added dropmelts at 204'--208 C.,after recrystallization from absolute alcohol +ethyl acetate.

The followingcompounds may be prepared in an analogous manner:

Melting point of hydrochloride B0111 point under H (free base (a).NHCHzHzNHC H CHzCHzCHzCH;

(c) OH;

1 Dihydrochloride.

EXAMPLE l0 boiling at [30 C., under 0.02 mm. pressure of mercury.

The l-cyanol -(fi-carbethoxyethyl )-benzocyclobutene used as startingmaterial may be obtained as follows:

l to 2 ml. of trimethylbenzyl ammonium hydroxide in tertiary butanolareadded in small portions to a mixture of l2.9 grams ofl-cyano-benzocyclobutene, 17 ml. of absolute tetrahydrofuran and 15.0grams of acrylethyl ester. The reac- 5 tion mixtures heats up to 70 C.,and is then allowed to stand overnight at room temperature. The reactionmixture is evaporated in vacuo at 40 C., and the ester extracted withmethylene chloride. The organic phase is washed successively with water,N-hydrochloric acid, sodium carbonate solution and water and dried oversodium sulfate, filtered and evaporated. The oily residue yields ondistillation l-cyano-l- (B-carbethoxyethyl)-benzocyclobutene of theformula CHgCHzCOzCzHr boiling at 12 l-l 23 C., under 0.07 mm. pressureof mercury.

EXAMPLE l l 9.6 grams of propargyl bromide in ml. of absolute acetoneare added dropwise to a mixture of l3 grams oflethylaminomethyl-benzocyclobutene (cf. example 5), 75 ml. of absoluteacetone and 25 grams of anhydrous potassium carbonate. When the additionis complete, the reaction mixture is stirred for 2 hours at roorntemperature, the potassium carbonate is filtered with suction and thefiltrate evaporated. The residue is taken up in ether and the amineextracted with 2N- hydrochloric acid. The base is liberated by theaddition of 2N- sodium hydroxide solution at 0 C., taken up in ether andwashed with water. The solution is dried over sodium sulfate, filteredand evaporated. The colorless oily residue yields on distillation l-[N-propargyl-ethylamino )-methyl ]-benzocyclobutene of the formula CHr-NCHz- C CH boiling at 65-67 C., under 0.03 mm. pressure of mercury. Bytreatment with hydrochloric acid in ethyl acetate the amine can beconverted into the crystalline hydrochloride melting at l 35-l 36 C.

EXAMPLE l2 CHrO CHzNHz boiling at 68-73 C., under 0.05 mm. pressure ofmercury.

For the preparation of the hydrochloride the amine is treated withhydrogen chloride in absolute ethyl acetate. The

colorless crystals are recrystallized from absolute ethyl al-'cohoH-ethyl acetate: melting point: l65-l 67 C.

The l-cyano-5-methoxy-benzocyclobutene used as starting material may beobtained as follows:

A mixture of 64.5 grams of 3-bromo-4-methoxybenzaldehyde, 60 grams ofmalonic acid, 120 ml. of absolute pyridine and 3 ml. of piperidine ismaintained at C., for 2 hours and then poured into a mixture of I75 ml.of concentrated hydrochloric acid and 300 grams of ice with stirring.

The acid which crystallizes out is filtered with suction and washed with25 ml. of hydrochloric acid of 10 percent strength and twice with 25 ml.of water each time. Recrystallization of the filter residue fromdimethylformamide-l-alcohol yields 3bromo-4-methoxy-cinnamic acidmelting at 241-243 C.

91.5 grams of 3bromo 4-methoxy-cinnamic acid are catalyticallyhydrogenated in 1,100 ml. of alcohol of 95percent strength in thepresence of 9 grams of Raney nickel at room temperature and under normalpressure. The catalyst is filtered ofi and the filtrate evaporated at 40C. at a water-jet vacuum. The ultraviolet spectrum of the crystallineresidue shows that the hydrogenation of 3-bromo-4-methoxy-cinnamic acidwas complete.

IOgrams of the so-obtained crude hydrocinnamic acid are boiled underreflux with about 20 ml. of thionyl chloride for 2 to 4hours. The clearsolution is freed from the excess thionyl chloride at 40 C. at awater-jet vacuum. The oily residue yields on distillation 7.8 grams of3-bromo-4-methoxy-phenylpropionyl chloride boiling at 133-136" C., under0.1 mm. pressure of mercury.

lOgrams of 3-bromo-4-methoxyphenyl-propionyl chloride are added dropwiseto a concentrated solution of aqueous ammonia with stin-ing andice-cooling. The amide which precipitates is filtered with suction andwashed with water. After drying in vacuo over calcium chloridecolorless, crude 3-bromo-4-methoxy-pheny1 propionamide 'is obtained. Forconversion into the nitrile the amide need not be purified any further.

25.8 grams of the so-prepared and dried amide are dissolved in 25 ml. ofabsolute pyridine and reacted with 21 grams of paratoluenesulfonicchloride in small portions at a temperature between and 40 C. withstirring. After the exothermic reaction has subsided, the solution isallowed to cool to room temperature and is then poured into a mixture ofice and water with stirring. v

The batch is stirred for about minutes at room temperature and thenitrile is then extracted with ether. The ethereal solution is washedwith water, ZN-sodium carbonate solution and again with water, driedover sodium sulfate. filtered and evaporated. The colorless oily residueyields on distillation 3- bromo-4methoxy-phenylpropionitrile of theformula CHgCHzCN boiling at l30-134 C. under 0.03 mm. pressure ofmercury.

22 grams of potassium are added in small portions to 250 ml. of absoluteliquid ammonia and a pinch of iron trinitrate. 25grams of3-bromo-4methoxy-phenylpropionitrile are added dropwise to the potassiumamide solution within 1 to 2 minutes and the reaction mixture is thenstirred for minutes. 40 grams of ammonium chloride are then introducedCHaO CN as a colorless liquid boiling at 105-1 15 C. under 0.15 mm.pressure of mercury.

EXAMPLE 1 3 4.1 grams of 1 -cyano-4:5-methy1enedioxy-benzocyclobutene in80 ml. of liquid ammonia and 80 ml. of absolute alcohol are hydrogenatedin a /&-liter autoclave in the presence of 0.5 gram of Raney nickelunder a hydrogen pressure of atmosphere at C. After about 30 minutes,the autoclave is allowed to cool, the pressure is released, the catalystfiltered ofl" and the filtrate evaporated at 30 C., at a water-jetvacuum. The residue is distilled and yields l-aminomethyl-4z5-methylenedioxy-benzocyclobutene of the formula boiling at C. under 0.1mm. pressure of mercury.

For the preparation of the hydrochloride the amine is treated withhydrogen chloride in absolute ethyl acetate. The colorless crystals arerecrystallized from absolute ethyl alcohol or water. Melting point: 265C., (DEC) The l-cyano-4:5: -methylenedioxy-benzocyclobutene used asstarting material may be obtained as follows:

A mixture of 76.3 grams of 6 -bromo-piperonal, 60 grams of malonic acid,ml. of absolute pyridine and 3 ml. of piperidine is maintained at 100C., for 2 hours and then poured into a mixture of 175 ml. ofconcentrated hydrochloric acid and 300 grams of ice with stining. Theacid which crystallizes out is filtered with suction and washed with 25ml. of hydrochloric acid of 10 percent strength and twice with 25 ml. ofwater each time Recrystallization of the filter residue fromdimethylformamide+alcohol yields 2-bromo-4:5: 5- methylenedioxy-cinnamicacid melting at 25 7260 C.

27.0 grams of 2 -bromo-4:5: -methylenedioxy-cinnamic acid arecatalytically hydrogenated in 100 ml. of N-sodium hydroxide solution and350 ml. of water in the presence of 3 grams of Raney nickel at roomtemperature and under atmospheric pressure. The catalyst is filtered oh,the filtrate evaporated at 40 C., at a water-jet vacuum and the residueacidified at 0 C. with concentrated hydrochloric acid. The ultravioletspectrum of the filtered, crystalline residue shows that thehydrogenation of 2 -bromo-4:S-methylenedioxy-cinnamic acid to thecorresponding hydrocinnamic acid was complete.

25 grams of the so-obtained crude hydrocinnamic acid are boiled underreflux for 2 hours with about 25 ml. of thionyl chloride and 50 ml. ofbenzene. The clear solution is evaporated at 40 C. at a water-jetvacuum. On distillation the oily residue yields 19.9 grams of2-bromo-4:5-methylendioxyphenyl-proplonyl chloride boiling at l50-152 C.under 0.18 mm. pressure of mercury.

19.9 grams of 2-bromo-4:S-methylenedioxy-phenyl-propionyl chloride in 40ml. of absolute tetrahydrofuran are added dropwise to 250 ml. of asolution of ammonia saturated at 0C. in absolute tetrahydrofuran withstirring and ice-cooling. The ammonium chloride which precipitates isfiltered with sucn'on after 3 hours and washed with chloroform. Thefiltrate is evaporated in vacuo. The residue taken up in chloroform iswashed with ice-water, 10.7 grams of 2 -bromo-4:5-methylenedioxyphenyl-propionamide melting at -1 53 C. crystallizing out.For conversion into the nitrile the amide need not be purified further.

12.7 grams of the so-prepared and dried amide are dissolved in 12 ml. ofabsolute pyridine and reacted with 9.8 grams ofpara-toluene-sulphochloride in small portions at a temperature between 0and 40 C. with stirring. After the exothermic reaction has subsided, thesolution is allowed to cool to room temperature and is then poured withstirring into a mixture of ice an water. The batch is stirred for about10 minutes at room temperature and the nitrile then extracted withether. The ethereal solution is washed with water, 2N-sodium carbonatesolution and again with water, dried-over sodium sulfate filtered andevaporated. On distillation the colorless oily residue yields 10.1 gramsof solid 2 -bromo-4:S-methylenedioxy-phenyl propionitrile of the formulaboiling at l30l32 C. under 0.04 mm. pressure of mercury and melting at73-76 C.

10.6 grams of potassium are added in small portions to 125 ml. ofabsolute liquid ammonia and a pinch of iron trinitrate. 12.6 grams ofpulverized 2 -bromo-4:S-methylenedioxy-phenylpropionitrile are added tothe potassium amide solution within 1 2 minutes and the reaction mixtureis then stirred for 15 minutes. 20 grams of ammonium chloride are thenintroduced cautiously. The ammonia is allowed to evaporate and 50 to 100ml. of water are then added to the residue. The organic material isextracted with ether. The etheral phase is washed five times with water,dried over sodium sulfate, filtered and evaporated. On distillation thesolid residue yields crystalline l-cyano-4:5-methylenedioxy-benzocyclobutene of boiling at l l5-120 C.under 0.10 mm. pressure of mercury. The compound can be recrystallizedfrom methyl alcohol; melting point: 84-87 C.

R GEN in which R stands for a member selected from the group consistingof hydroxyl, lower alkoxy, lower alkanoyloxy, benzoyloxy, phenyl-loweralkanoyloxy, amino, mono-lower alkylamino, di-lower alkylamino andtrifluoromethyl and R stands for a member selected from the groupconsisting of hydrogen, lower alkyl, hydroxy-lower alkyl and carbo-loweralkoxy-lower alkyl.

2. A compound as claimed in claim 1, wherein R represents hydrogen.

3. A compound as claimed in claim I, wherein R stands for a memberselected from the group consisting of hydroxyl, lower alkoxy andtrifluoromethyl, and R stands for hydrogen.

4 A compound as claimed in claim 1, wherein R stands for lower alkoxyand R stands for hydrogen.

5. A compound as claimed in claim 1, which compound is the l-cyano-5-methoxybenzocyclobutene.

e w w

2. A compound as claimed in claim 1, wherein R'' represents hydrogen. 3.A compound as claimed in claim 1, wherein R stands for a member selectedfrom the group consisting of hydroxyl, lower alkoxy and trifluoromethyl,and R'' stands for hydrogen.
 4. A compound as claimed in claim 1,wherein R stands for lower alkoxy and R'' stands for hydrogen.
 5. Acompound as claimed in claim 1, which compound is the 1-cyano-5-methoxybenzocyclobutene.